title: Population-prevalent desmosomal mutations predisposing to arrhythmogenic right ventricular cardiomyopathy.
abstract: BACKGROUND
  Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a progressive myocardial disorder caused by mutations of desmosomal cell adhesion proteins. The prevalence of these variants in the general population is unknown.
  
  
  OBJECTIVE
  This study examined the spectrum and population prevalence of desmosomal mutations predisposing to ARVC in Finland.
  
  
  METHODS
  We screened 29 Finnish ARVC probands for mutations in the DSP, DSG2, and DSC2 genes. All Finnish-type ARVC-associated mutations, including those 3 previously identified in PKP2 in the same patient group, were analyzed in the population-based Health 2000 cohort of 6,334 individuals and tested for association with electrocardiographic variables.
  
  
  RESULTS
  We detected 2 novel mutations: DSG2 3059_3062delAGAG and DSP T1373A. DSG2 3059_3062delAGAG was present in a family with 5 mutation carriers. The endomyocardial samples of the DSG2 deletion carrier showed reduced immunoreactive signal for desmoglein-2, plakophilin-2, plakoglobin, and desmoplakin. DSP T1373A was found in 1 proband with typical right ventricular disease and exercise-related ventricular tachycardia. In the population sample, the collective prevalence of all 5 mutations identified in the 29 ARVC patients (PKP2 Q62K, Q59L, N613K, DSG2 3059_3062delAGAG, and DSP T1373A) was 31 of 6,334 individuals, or 0.5%. The apparent founder mutation PKP2 Q59L is present in 0.3% of Finns and was previously shown to have an approximately 20% disease penetrance.
  
  
  CONCLUSIONS
  One of 200 Finns carries a desmosomal mutation that may predispose to ARVC and its clinical sequelae. ARVC-associated mutations may thus be more prevalent in the population than expected based on the published ARVC prevalence data.
authors.affiliation: Research Program for Molecular Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Annukka M
authors.initials: AM
authors.lastname: Lahtinen
authors.forename: Eero
authors.initials: E
authors.lastname: Lehtonen
authors.forename: Annukka
authors.initials: A
authors.lastname: Marjamaa
authors.forename: Maija
authors.initials: M
authors.lastname: Kaartinen
authors.forename: Tiina
authors.initials: T
authors.lastname: Heliö
authors.forename: Kimmo
authors.initials: K
authors.lastname: Porthan
authors.forename: Lasse
authors.initials: L
authors.lastname: Oikarinen
authors.forename: Lauri
authors.initials: L
authors.lastname: Toivonen
authors.forename: Heikki
authors.initials: H
authors.lastname: Swan
authors.forename: Antti
authors.initials: A
authors.lastname: Jula
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.forename: Veikko
authors.initials: V
authors.lastname: Salomaa
authors.forename: Kimmo
authors.initials: K
authors.lastname: Kontula
mesh_terms: D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics*; D002448:Cell Adhesion / Q000235:genetics; D051301:Desmoglein 2 / Q000235:genetics; D051180:Desmoplakins / Q000235:genetics; D003896:Desmosomes / Q000235:genetics*; D004562:Electrocardiography; D005387:Finland; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005828:Genetics, Population; D006579:Heterozygote; D006801:Humans; D051191:Plakophilins / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: C495314:DSG2 protein, human; D051301:Desmoglein 2; D051180:Desmoplakins; C495337:PKP2 protein, human; D051191:Plakophilins